Combinatorial one-pot chemoenzymatic synthesis of heparin

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Authors
Bhaskar, Ujjwal
Li, Guoyun
Fu, Li
Onishi, Akihiro
Suflita, Mathew
Dordick, Jonathan S.
Linhardt, Robert J.
Issue Date
2015-05-20
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Abstract
Contamination in heparin batches during early 2008 has resulted in a significant effort to develop a safer bioengineered heparin using bacterial capsular polysaccharide heparosan and recombinant enzymes derived from the heparin/heparan sulfate biosynthetic pathway. This requires controlled chemical N-deacetylation/N-sulfonation of heparosan followed by epimerization of most of its glucuronic acid residues to iduronic acid and O-sulfation of the C2 position of iduronic acid and the C3 and C6 positions of the glucosamine residues. A combinatorial study of multi-enzyme, one-pot, in vitro biocatalytic synthesis, carried out in tandem with sensitive analytical techniques, reveals controlled structural changes leading to heparin products similar to animal-derived heparin active pharmaceutical ingredients. Liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy analysis confirms an abundance of heparin's characteristic trisulfated disaccharide, as well as 3-O-sulfo containing residues critical for heparin binding to antithrombin III and its anticoagulant activity. The bioengineered heparins prepared using this simplified one-pot chemoenzymatic synthesis also show in vitro anticoagulant activity.
Description
Carbohydrate Polymers, 122, 399–407
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Full Citation
Combinatorial one-pot chemoenzymatic synthesis of heparin, U. Bhaskar, G. Li, L. Fu, A. Onishi, M. Suflita, J. S. Dordick, R. J. Linhardt, Carbohydrate Polymers, 122, 399–407, 2015.
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Elsevier
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ISSN
1448617
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